Role of innate immune tolerance in the pathogenesis of Lyme disease

根据定义，能够在宿主中持续存在以引起长期感染的细菌能够逃避宿主 免疫防御虽然持续感染的建立可以使细菌受益，但在某些情况下， 细菌本身造成的损害很小，允许建立长期感染可能更多 对宿主有益的免疫系统。伯氏疏螺旋体， 莱姆病不产生毒素或其他被认为会损害宿主的毒力因子。相反， 莱姆病的表现被认为是对生物体的免疫反应的结果。在其 天然的Peromyscus小鼠宿主，尽管事实上， 一旦被感染，该生物体将在动物的一生中持续存在。在人类和近亲繁殖的小鼠中（它们确实发展了 炎症被认为是由先天免疫系统的受体引发的， 系统在体外，先天免疫系统识别B的受体丧失。burgdorferi，如toll 受体2（TLR2）或Nod2导致炎症反应降低。然而，动物体内研究 缺乏这些受体或其衔接分子并不能减少炎症，在许多情况下， 实际上导致了炎症的加剧。我们假设宿主进化出了抑制 随着时间的推移，免疫反应，并在长期接触的过程中，这些受体发挥更大的作用， 在引发先天免疫耐受而不是激活急性炎症途径中起重要作用。在 初步研究表明，巨噬细胞暴露于B. burgdorferi可以减少 在再暴露于生物体时，本发明的组合物可抑制炎性细胞因子并增加抗炎性细胞因子的释放。 在这项建议中，我们将首先确定参与介导先天免疫的途径和机制， 对B的耐受性。burgdorferi。我们将研究这两个途径，已确定在发挥作用的宽容 与其他药物（如脂多糖）的反应，并进行无偏倚的研究，以确定新的机制。在 目的2：建立天然免疫耐受在莱姆病发病中的作用的动物模型。 我们将测试离体和体内系统，以分离B期间不同途径的作用。burgdorferi 感染这些实验的成功完成将为一种新的宿主策略提供原理上的证明 防御（互利共生或“良性忽视”）对被认为是病原体的生物体，并建立一个 先天免疫耐受存在的理由。

Bacteria that are able to persist in hosts to cause long term infections are, by definition, able to evade host immune defenses. While establishment of persistent infection can benefit the bacteria, in certain cases where the bacteria itself causes little damage, allowing the establishment of prolonged infection may be more beneficial to the host than continued attack by the immune system. Borrelia burgdorferi, the causative agent of Lyme disease, produces no toxins or other virulence factors thought to damage the host. Instead, most of the manifestations of Lyme disease are thought to be the result of the immune response to the organism. In its natural Peromyscus mouse host, little or no reaction to the organism is typically seen despite the fact that, once infected, the organism persists for the life of the animal. In humans and inbred mice (which do develop immune responses to the organism), inflammation is thought to be initiated by receptors of the innate immune system. In vitro, loss of receptors of the innate immune system that recognize B. burgdorferi such as toll-like receptor 2 (TLR2) or Nod2 results in a decrease inflammatory response. However, in vivo studies of animals deficient in these receptors or their adaptor molecules have not reduced inflammation and in many cases, have actually resulted in increased inflammation. We hypothesize that the host has evolved methods for dampening the immune response over time and that during the course of prolonged exposure, these receptors play a more important role in triggering innate immune tolerance, rather than activating acute inflammatory pathways. In preliminary studies, we have shown that exposure of macrophages to B. burgdorferi can reduce release of inflammatory cytokines and increase release of anti-inflammatory cytokines upon re-exposure to the organism. In this proposal, we will first identify pathways and mechanisms involved in mediating innate immune tolerance to B. burgdorferi. We will study both pathways that have been identified in playing a role in tolerance to other agents (e.g. lipopolysaccharide) as well as perform unbiased studies to identify new mechanisms. In Aim 2, we will develop animal models to study the importance of innate immune tolerance in Lyme disease. We will test both ex vivo and in vivo systems for isolating the role of different pathways during B. burgdorferi infection. Successful completion of these experiments will provide proof of principle for a new strategy of host defense (mutualism or “benign neglect”) against organisms that are considered pathogens and establish a rationale for the existence of innate immune tolerance.